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Abstract: FR-PO583

CD19 CAR-T Cells Protect Against the Development of ANCA-Induced Necrotizing Crescentic Glomerulonephritis in a Mouse Model

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Lodka, Dörte, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Rousselle, Anthony, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Kettritz, Ralph, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Zschummel, Maria, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany
  • Bunse, Mario, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Berlin, Germany
  • Schreiber, Adrian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background

ANCA-induced vasculitis and NCGN are potentially life-threatening and current therapeutic approaches are largely based on cytotoxic drugs or B-cell-depleting antibodies. Chimeric antigen receptor T cells (CAR T cells) are genetically modified T cells that express a protein consisting of intracellular T cell receptor domains that are coupled to an extracellularly located antibody domain. The antibody specificity determines which target cells are recognized and destroyed by the CAR T cells. The use of CAR-T cells in autoimmune diseases is a promising new therapeutic approach. Since ANCA are implicated in ANCA-associated vasculitides (AAVs), depletion of ANCA-producing B cells may be an effective AAV therapy. We tested the hypothesis that CD19 CAR T cells deplete B cells, including MPO-ANCA-producing B cells, thereby protecting from MPO-ANCA induced necrotizing crescentic glomerulonephritis (NCGN).

Methods

Anti-MPO NCGN was induced by immunization of MPO-/--mice with murine MPO, followed by irradiation and transplantation of hematopoietic cells from WT mice. In addition, CD19 CAR-T cells and SP6 CAR-T cells (control CAR) were administered. Effects on disease severity were analyzed by histological examination of kidney sections and by spleen, blood and bone marrow flow cytometry.

Results

CD19 CAR T cells showed efficient immigration and stable persistence in the transplanted animals, as they were detectable in bone marrow, spleen and peripheral blood after two and five weeks. In addition, mice receiving CD19 CAR T cells had significantly reduced amounts of CD19-expressing endogenous B cells compared to SP6 CAR T mice at 5 weeks in bone marrow (0.03% vs. 6.68%), spleen (0.05% vs. 60.7%) and peripheral blood (0.004% vs. 38.3%) accompanied by decreased anti-MPO titer. Finally, histology revealed a reduction in both crescentic (0.49% vs. 10.83%) and necrotic (0% vs. 6.04%) glomeruli in mice receiving CD19 CAR T cells compared to SP6 CAR T mice at 5 weeks, thus showing a protection from NCGN induction.

Conclusion

Our data suggest that depletion of CD19-expressing B cells by administration of CD19 CAR-T cells is an effective therapeutic option in murine anti-MPO-induced NCGN.

Funding

  • Government Support – Non-U.S.